Noise-induced hearing loss affects more than 25 million adults, with the majority of these cases suspected to be the result of exposure to environmental sounds. Importantly, some humans with no overt indications of hearing loss have extraordinary difficulty processing speech in noisy environments, but only recently has a potential explanation emerged. Noise exposure at sound pressure levels that cause a temporary threshold shift but no permanent threshold shift results in a loss of ribbon synapses (synaptopathy) without any hair cell loss, and a reduction in the amplitude of auditory brainstem response (ABR) Wave I. Low spontaneous rate (LSR) auditory nerve fibers (ANFs) seem particularly susceptible to this loss. While these effects are well described in rodents, it is not clear that they occur in humans. It is impossible to demonstrate synaptopathy directly in humans. We propose to bridge this gap by performing parallel experiments in humans and an animal model that shares great similarity, both anatomically and mechanistically, with humans: macaques. Our recently developed macaque model of synaptopathy shares some features with the established rodent model, but also reveals differences in susceptibility, which may also be present in other primates such as humans. We propose parallel experiments in control and noise-exposed macaques (without and with synaptopathy, respectively) and in two groups of humans with normal hearing thresholds: a control group and a noise-exposed human cohort. Our overarching hypothesis is that synaptopathy caused by noise exposure impairs temporal processing, resulting in deficits in physiological (Aim1) and behavioral (Aims 2) metrics of suprathreshold stimulus processing, and these deficits will be correlated with the amount of synaptopathy, which will be verified by histology and ANF recordings in macaques (Aim 3). We predict that physiological measures of processes that involve LSR fibers (including coding of modulation in suprathreshold sounds and masked sounds, middle ear muscle reflexes, and recovery from forward masking) will be impaired in subjects with synaptopathy relative to normal subjects (Aim 1). We predict that behaviors that require temporal cues to process simple stimuli (detection of amplitude modulation, suprathreshold masked detection, forward masking thresholds, and the contribution of temporal cues to the detection of suprathreshold tones in noise) and complex stimuli (speech-in-noise and spatial-attention tasks, and release from masking) will be impaired in subjects with synaptopathy (Aim 2). The synaptopathy will be histologically verified and its ANF correlates (loss of LSR fibers) verified directly in macaques (Aim 3). The results of these studies will reveal sensitive physiological and behavioral markers of synaptopathy, validated by histological and neurophysiological findings in macaques. These parallel studies in humans and macaques will elucidate the functional consequences of synaptopathy on auditory perception. Results of our coordinated research program will be used to develop reliable, clinically viable physiological and behavioral indicators of human synaptopathy.
Prolonged noise exposure in rodents that causes temporary, but not permanent, threshold shifts reduces the number of inner hair cell ribbon synapses and the number of high-threshold, low-spontaneous rate afferents, but it is not clear if the same effects are seen in humans. By combining macaque anatomical, behavioral, and physiological studies with human behavioral and physiological studies, we propose to show that similar synaptopathy occurs in humans. By working in parallel in both humans and macaques, we hope to elucidate the behavioral consequences of synaptopathy in human perception of simple and complex stimuli in the real world, and to identify clinical tests that are sensitive to the presence of synaptopathy without hair cell loss.
